tbuckley/cabot-search huggingface dataset:
NIR-IIb fluorescence-image guided synergistic surgery/starvation/chemodynamic therapy: an innovative treatment paradigm for malignant non-small cell lung cancers
Authors: Xuejiao Han, Yingtao Zhong, Chao Mi, Zhiguo He, Jingsi Gu, Xiaoyong Dai, Chenguang Ma, Chunyan Feng, Huaqing Chen, Zebin Lan, Zhiyong Guo, Laiqiang Huang, Baozhu Zhang, Bing Guo, Qingwei Meng
Journal: Theranostics (2023)

Currently, the prognosis and survival rate for patients bearing non-small cell lung cancer (NSCLC) is still quite poor, mainly due to lack of efficient theranostic paradigms to exert in time diagnostics and therapeutics.
Inhibition of Th17 cells by donepezil ameliorates experimental lung fibrosis and pulmonary hypertension
Authors: Yuan Guo, Ziyu He, Zhu Chen, Fengling Chen, Chengming Wang, Wanlu Zhou, Jie Liu, Hao Liu, Ruizheng Shi
Journal: Theranostics (2023)

Pulmonary hypertension (PH) secondary to lung fibrosis belongs to WHO Group III, one of the most common subgroups of PH; however, it lacks effective treatment options. Cholinesterase inhibitor donepezil (DON) has been shown to effectively improve Group I PH. However, its effects on Group III PH are unknown.
CSF2RB overexpression promotes the protective effects of mesenchymal stromal cells against ischemic heart injury
Authors: Tingting Qi, Xiaoming Xu, Yongzhen Guo, Yunlong Xia, Lu Peng, Congye Li, Fengyue Ding, Chao Gao, Miaomiao Fan, Min Yu, Huishou Zhao, Yuan He, Wenli Li, Chunxu Hai, Erhe Gao, Xing Zhang, Feng Gao, Yanhong Fan, Wenjun Yan, Ling Tao
Journal: Theranostics (2023)

Aims:The invasive intramyocardial injection of mesenchymal stromal cells (MSCs) allows for limited repeat injections and shows poor therapeutic efficacy against ischemic heart failure.Intravenous injection is an alternative method because this route allows for repeated, noninvasive, and easy delivery.However, the lack of targeting of MSCs hinders the ability of these cells to accumulate in the ischemic area after intravenous injections.We investigated whether and how the overexpression of colony-stimulating factor 2 receptor beta subunit (CSF2RB) may regulate the cardiac homing of MSCs and their cardioprotective effects against ischemic heart failure.Methods and Results: Adult mice were subjected to myocardial ischemia/reperfusion (MI/R) or sham operations.We observed significantly higher CSF2 protein expression and secretion by the ischemic heart from 1 day to 2 weeks after MI/R.Mouse adipose tissue-derived MSCs (ADSCs) were infected with adenovirus harboring CSF2RB or control adenovirus.Enhanced green fluorescent protein (EGFP)-labeled ADSCs were intravenously injected into MI/R mice every three days for a total of 7 times.Compared with ADSCs infected with control adenovirus, intravenously delivered ADSCs overexpressing CSF2RB exhibited markedly increased cardiac homing.Histological analysis revealed that CSF2RB overexpression significantly enhanced the ADSC-mediated proangiogenic, antiapoptotic, and antifibrotic effects.More importantly, ADSCs overexpressing CSF2RB significantly increased the left ventricular ejection fraction and cardiac contractility/relaxation in MI/R mice.In vitro experiments demonstrated that CSF2RB overexpression increases the migratory capacity and reduces the hypoxia/reoxygenation-induced apoptosis of ADSCs.We identified STAT5 phosphorylation as the key mechanism underlying the effects of CSF2RB on promoting ADSC migration and inhibiting ADSC apoptosis.RNA sequencing followed by cause-effect analysis revealed that CSF2RB overexpression increases the expression of the ubiquitin ligase RNF4.Coimmunoprecipitation and coimmunostaining experiments showed that RNF4 binds to phosphorylated STAT5.RNF4 knockdown reduced STAT5 phosphorylation as well as the antiapoptotic and promigratory actions of ADSCs overexpressing CSF2RB.
Transcription factor TOX maintains the expression of Mst1 in controlling the early mouse NK cell development
Authors: Liang Luo, Peiran Feng, Quanli Yang, Wenkai Lv, Wanqing Meng, Zhinan Yin, Zhizhong Li, Guodong Sun, Zhongjun Dong, Meixiang Yang
Journal: Theranostics (2023)

Rationale: TOX is a DNA-binding factor required for the development of multiple immune cells and the formation of lymph nodes. However, the temporal regulation mode of TOX on NK cell development and function needs to be further explored. Methods: To investigate the role of TOX in NK cells at distinct developmental phases, we deleted TOX at the hematopoietic stem cell stage (Vav-Cre), NK cell precursor (CD122-Cre) stage and late NK cell developmental stage (Ncr1-Cre), respectively. Flow cytometry was used to detect the development and functional changes of NK cell when deletion of TOX. RNA-seq was used to assess the differences in transcriptional expression profile of WT and TOX-deficient NK cells. Published Chip-seq data was exploited to search for the proteins directly interact with TOX in NK cells. Results: The deficiency of TOX at the hematopoietic stem cell stage severely retarded NK cell development. To a less extent, TOX also played an essential role in the physiological process of NKp cells differentiation into mature NK cells. Furthermore, the deletion of TOX at NKp stage severely impaired the immune surveillance function of NK cells, accompanied by down-regulation of IFN-γ and CD107a expression. However, TOX is dispensable for mature NK cell development and function. Mechanistically, by combining RNA-seq data with published TOX ChIP-seq data, we found that the inactivation of TOX at NKp stage directly repressed the expression of Mst1, an important intermediate kinase in Hippo signaling pathway. Mst1 deficient at NKp stage gained the similar phenotype with Toxfl/flCD122Cre mice. Conclusion: In our study, we conclude that TOX coordinates the early mouse NK cell development at NKp stage by maintaining the expression of Mst1. Moreover, we clarify the different dependence of the transcription factor TOX in NK cells biology.
Hypoxia Induces M2 Macrophages to Express VSIG4 and Mediate Cardiac Fibrosis After Myocardial Infarction
Authors: Yan Wang, Yu Zhang, Jiao Li, Chaofu Li, Ranzun Zhao, Changyin Shen, Weiwei Liu, Jidong Rong, Zhenglong Wang, Junbo Ge, Bei Shi
Journal: Theranostics (2023)

M2 macrophage-mediated tissue repair plays an important role in acute myocardial infarction (AMI).Additionally, VSIG4, which is mainly expressed on tissue-resident and M2 macrophages, is crucial for the regulation of immune homeostasis; however, its effects on AMI remain unknown.In this study, we aimed to investigate the functional significance of VSIG4 in AMI using VSIG4 knockout and adoptive bone marrow transfer chimeric models.We also determined the function of cardiac fibroblasts (CFs) through gain-or loss-of-function experiments.We showed that VSIG4 promotes scar formation and orchestrates the myocardial inflammatory response after AMI, while also promoting TGF-β1 and IL-10.Moreover, we revealed that hypoxia promotes VSIG4 expression in cultured bone marrow M2 macrophages, ultimately leading to the conversion of CFs to myofibroblasts.Our results reveal a crucial role for VSIG4 in the process of AMI in mice and provide a potential immunomodulatory therapeutic avenue for fibrosis repair after AMI.
Platelets promote CRC by activating the C5a/C5aR1 axis via PSGL-1/JNK/STAT1 signaling in tumor-associated macrophages
Authors: Xueqin Li, Xin Chen, Shengzhe Gong, Jie Zhao, Chen Yao, Hanyong Zhu, Rui Xiao, Yongqin Qin, Rongqing Li, Na Sun, Xiangyang Li, Fuxing Dong, Tingting Zhao, Yuchen Pan, Jing Yang
Journal: Theranostics (2023)

Rationale: Platelets can influence the progression and prognosis of colorectal cancer (CRC) through multiple mechanisms, including crosstalk with tumor-associated macrophages (TAMs).However, the mechanisms underlying the crosstalk between platelets and TAMs remain unclear.The present study aimed to investigate the role of intratumoral platelets in regulating the function of TAMs and to identify the underlying mechanisms.Methods: The interaction of platelets with macrophages was assessed in the presence or absence of the indicated compounds in vivo.An azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC mouse model was used to investigate the role of platelets in controlling CRC development.Multiplexed immunofluorescence staining, fluorescence-activated cell sorting (FACS), and RNA sequence analysis were used to examine the changes in TAMs.TAMs and bone marrow-derived macrophages (BMDMs) were treated with the indicated compounds or siRNA against specific targets, and the expression levels of signal transducer and activator of transcription 1 (STAT1), c-Jun N-terminal kinase (JNK), and P-selectin glycoprotein ligand-1 (PSGL-1) were measured by Western blotting.The mRNA expression levels of complement 5 (C5), complement 5a receptor 1 (C5ar1), Arginase 1 (Arg1) and Il10 were measured by real-time RT-PCR, and the complement 5a (C5a) concentration was measured by ELISA.The dual-luciferase reporter assay and ChIP assay were performed to examine the potential regulatory mechanisms of platelet induction of C5 transcription in TAMs.Results: In our study, we found that an increase in platelets exacerbated CRC development, while inhibiting platelet adhesion attenuated tumor growth.Platelets signal TAMs through P-selectin (CD62P) binding to PSGL-1 expressed on TAMs and activating the JNK/STAT1 pathway to induce the transcription of C5 and the release of C5a, shifting TAMs toward a protumor phenotype.Inhibiting the C5a/C5aR1 axis or PSGL-1 significantly reduced CRC growth.Conclusions: An increase in intratumoral platelets promoted CRC growth and metastasis by CD62P binding to PSGL-1 expressed on TAMs, leading to JNK/STAT1 signaling activation, which promoted C5 transcription and activated the C5a/C5aR1 axis in TAMs.Our study examined the mechanism of the crosstalk between platelets and TAMs to exacerbate CRC development and proposed a potential therapeutic strategy for CRC patients.
Tumor protease-activated theranostic nanoparticles for MRI-guided glioblastoma therapy
Authors: Ching-Hsin Huang, Edwin Chang, Li Zheng, Joe Gerald Jesu Raj, Wei Wu, Laura J. Pisani, Heike E. Daldrup-Link
Journal: Theranostics (2023)

Rationale: As a cancer, Glioblastoma (GBM) is a highly lethal and difficult-to-treat. With the aim of improving therapies to GBM, we developed novel and target-specific theranostic nanoparticles (TNPs) that can be selectively cleaved by cathepsin B (Cat B) to release the potent toxin monomethyl auristatin E (MMAE). Methods: We synthesized TNPs composed of a ferumoxytol-based nanoparticle carrier and a peptide prodrug with a Cat-B-responsive linker and the tubulin inhibitor MMAE. We hypothesized that intratumoral Cat B can cleave our TNPs and release MMAE to kill GBM cells. The ferumoxytol core enables in vivo drug tracking with magnetic resonance imaging (MRI). We incubated U87-MG GBM cells with TNPs or ferumoxytol and evaluated the TNP content in the cells with transmission electron microscopy and Prussian blue staining. In addition, we stereotaxically implanted 6- to 8-week-old nude mice with U87-MG with U87-MG GBM cells that express a fusion protein of Green Fluorescence Protein and firefly Luciferase (U87-MG/GFP-fLuc). We then treated the animals with an intravenous dose of TNPs (25 mg/kg of ferumoxytol, 0.3 mg/kg of MMAE) or control. We also evaluated the combination of TNP treatment with radiation therapy. We performed MRI before and after TNP injection. We compared the results for tumor and normal brain tissue between the TNP and control groups. We also monitored tumor growth for a period of 21 days. Results: We successfully synthesized TNPs with a hydrodynamic size of 41 ± 5 nm and a zeta potential of 6 ± 3 mV. TNP-treated cells demonstrated a significantly higher iron content than ferumoxytol-treated cells (98 ± 1% vs. 3 ± 1% of cells were iron-positive, respectively). We also found significantly fewer live attached cells in the TNP-treated group (3.8 ± 2.0 px2) than in the ferumoxytol-treated group (80.0 ± 14.5 px2, p < 0001). In vivo MRI studies demonstrated a decline in the tumor signal after TNP (T2= 28 ms) but not control (T2= 32 ms) injections. When TNP injection was combined with radiation therapy, the tumor signals dropped further (T2 = 24 ms). The combination therapy of radiation therapy and TNPs extended the median survival from 14.5 days for the control group to 45 days for the combination therapy group. Conclusion: The new cleavable TNPs reported in this work accumulate in GBM, cause tumor cell death, and have synergistic effects with radiation therapy.
Histone H3K27 methyltransferase EZH2 regulates apoptotic and inflammatory responses in sepsis-induced AKI
Authors: Bojun Li, Yuqi Xia, Shuqin Mei, Zehua Ye, Baofeng Song, Xinzhou Yan, Fangyou Lin, Ting Rao, Weimin Yu, Changlin Mei, Jiayi Lv, Ming Wu, Zhiguo Mao, Xiangjun Zhou, Fan Cheng
Journal: Theranostics (2023)

Rationale: The role of histone methylation modifications in renal disease, particularly in sepsis-induced acute kidney injury (AKI), remains unclear. This study aims to investigate the potential involvement of the histone methyltransferase zeste homolog 2 (EZH2) in sepsis-induced AKI and its impact on apoptosis and inflammation. Methods: We first examined the expression of EZH2 in the kidney of sepsis-induced AKI (LPS injection) mice and LPS-stimulated tubular epithelial cells. We next constructed the EZH2 knockout mice to further confirm the effects of EZH2 on apoptosis and inflammatory response in AKI. And the inflammatory level of epithelial cells can be reflected by detecting chemokines and the chemotaxis of macrophages. Subsequently, we constructed the EZH2 knocked-down cells again and performed Chromatin Immunoprecipitation sequencing to screen out the target genes regulated by EZH2 and the enrichment pathway. Then we confirmed the EZH2 target gene and its regulatory pathway in vivo and in vitro experiments. Experimental results were finally confirmed using another in vivo model of sepsis-induced AKI (cecal perforation ligation). Results: The study found that EZH2 was upregulated in sepsis-induced AKI and that silencing EZH2 could reduce renal tubular injury by decreasing apoptosis and inflammatory response of tubular epithelial cells. EZH2 knockout mice showed significantly reduced renal inflammation and macrophage infiltration. Chromatin immunoprecipitation sequencing and polymerase chain reaction identified Sox9 as a target of EZH2. EZH2 was found to be enriched on the promoter of Sox9. Silencing EZH2 resulted in a significant increase in the transcriptional level of Sox9 and activation of the Wnt/β-catenin signaling pathway. The study further reversed the effects of EZH2 silencing by silencing Sox9 or administering the Wnt/β-catenin inhibitor icg001. It was also found that Sox9 positively regulated the expression of β-catenin and its downstream pathway-related genes. Finally, the study showed that the EZH2 inhibitor 3-deazaneplanocin A significantly alleviated sepsis-induced AKI. Conclusion: Our results indicate that silencing EZH2 can protect renal function by relieving transcriptional inhibition of Sox9, activating the Wnt/β-catenin pathway, and attenuating tubular epithelial apoptosis and inflammatory response of the renal interstitium. These results highlight the potential therapeutic value of targeting EZH2 in sepsis-induced AKI.
A novel role of master regulator transcription factor in anti-tumor immunity and cancer immunotherapy
Authors: Uttam K. Sinha, De-Chen Lin
Journal: Theranostics (2023)

Gene expression network in cancer cells is orchestrated by a small number of master regulator transcription factors (MRTFs), which play a prominent role in regulating cancer intrinsic hallmarks, such as sustaining proliferative signaling, evading growth suppressors, resisting cell death, etc. A new study reports a new role of one MRTF, KLF5, in regulating tumor microenvironment in an extrinsic manner. These findings not only reveal novel mechanistic underpinnings of tumor evasion from immune destruction but also broaden our understanding of the transcriptional deregulation in cancer biology.
The lysophosphatidic acid-regulated signal transduction network in ovarian cancer cells and its role in actomyosin dynamics, cell migration and entosis
Authors: Kaire Ojasalu, Sonja Lieber, Anna M. Sokol, Andrea Nist, Thorsten Stiewe, Imke Bullwinkel, Florian Finkernagel, Silke Reinartz, Sabine Müller-Brüsselbach, Robert Grosse, Johannes Graumann, Rolf Müller
Journal: Theranostics (2023)

Lysophosphatidic acid (LPA) species accumulate in the ascites of ovarian high-grade serous cancer (HGSC) and are associated with short relapse-free survival.LPA is known to support metastatic spread of cancer cells by activating a multitude of signaling pathways via G-protein-coupled receptors of the LPAR family.Systematic unbiased analyses of the LPA-regulated signal transduction network in ovarian cancer cells have, however, not been reported to date.Methods: LPA-induced signaling pathways were identified by phosphoproteomics of both patient-derived and OVCAR8 cells, RNA sequencing, measurements of intracellular Ca 2+ and cAMP as well as cell imaging.The function of LPARs and downstream signaling components in migration and entosis were analyzed by selective pharmacological inhibitors and RNA interference.Results: Phosphoproteomic analyses identified > 1100 LPA-regulated sites in > 800 proteins and revealed interconnected LPAR1, ROCK/RAC, PKC/D and ERK pathways to play a prominent role within a comprehensive signaling network.These pathways regulate essential processes, including transcriptional responses, actomyosin dynamics, cell migration and entosis.A critical component of this signaling network is MYPT1, a stimulatory subunit of protein phosphatase 1 (PP1), which in turn is a negative regulator of myosin light chain 2 (MLC2).LPA induces phosphorylation of MYPT1 through ROCK (T853) and PKC/ERK (S507), which is majorly driven by LPAR1.Inhibition of MYPT1, PKC or ERK impedes both LPA-induced cell migration and entosis, while interference with ROCK activity and MLC2 phosphorylation selectively blocks entosis, suggesting that MYPT1 figures in both ROCK/MLC2-dependent and -independent pathways.We finally show a novel pathway governed by LPAR2 and the RAC-GEF DOCK7 to be indispensable for the induction of entosis. Conclusion:We have identified a comprehensive LPA-induced signal transduction network controlling LPA-triggered cytoskeletal changes, cell migration and entosis in HGSC cells.Due to its pivotal role in this network, MYPT1 may represent a promising target for interfering with specific functions of PP1 essential for HGSC progression.
PRL3 as a therapeutic target for novel cancer immunotherapy in multiple cancer types
Authors: Pei Ling Chia, Koon Hwee Ang, Min Thura, Qi Zeng
Journal: Theranostics (2023)

Phosphatase of Regenerating Liver-3 (PRL3) was discovered in 1998 and was subsequently found to be correlated with cancer progression and metastasis in 2001.Extensive research in the past two decades has produced significant findings on PRL3-mediated cancer signaling and functions, as well as its clinical relevance in diverse types of cancer.PRL3 has been established to play a role in many cancer-related functions, including but not limited to metastasis, proliferation, and angiogenesis.Importantly, the tumor-specific expression of PRL3 protein in multiple cancer types has made it an attractive therapeutic target.Much effort has been made in developing PRL3-targeted therapy with small chemical inhibitors against intracellular PRL3, and notably, the development of PRL3-zumab as a novel cancer immunotherapy against PRL3.In this review, we summarize the current understanding of the role of PRL3 in cancer-related cellular functions, its prognostic value, as well as perspectives on PRL3 as a target for unconventional immunotherapy in the clinic with PRL3-zumab.
Selective ablation of TRA-1-60<sup>+</sup> pluripotent stem cells suppresses tumor growth of prostate cancer
Authors: Jordan M. White, Nicholas Ramos, Allen-Dexter Saliganan, Joon-Yong Chung, Meghan Bell, Jacob Lindquist, Kayla Conner, Wendy N. Wiesend, Michael Schopperle, Steve M. Patrick, Seongho Kim, Elisabeth I. Heath, Freddy E. Escorcia, Nerissa T. Viola
Journal: Theranostics (2023)

Purpose: TRA-1-60 (TRA) is an established transcription factor of embryonic signaling and a well-known marker of pluripotency.It has been implicated in tumorigenesis and metastases, is not expressed in differentiated cells, which makes it an appealing biomarker for immunopositron emission tomography (immunoPET) imaging and radiopharmaceutical therapy (RPT).Herein, we explored the clinical implications of TRA in prostate cancer (PCa), examined the potential of TRA-targeted PET to specifically image TRA + cancer stem cells (CSCs) and assessed response to the selective ablation of PCa CSCs using TRA-targeted RPT.Experimental Design: First, we assessed the relationship between TRA (PODXL) copy number alterations (CNA) and survival using publicly available patient databases.The anti-TRA antibody, Bstrongomab, was radiolabeled with Zr-89 or Lu-177 for immunoPET imaging and RPT in PCa xenografts.Radiosensitive tissues were collected to assess radiotoxicity while excised tumors were examined for pathologic treatment response.Results: Patients with tumors having high PODXL CNA exhibited poorer progression-free survival than those with low PODXL, suggesting that it plays an important role in tumor aggressiveness.TRA-targeted immunoPET imaging specifically imaged CSCs in DU-145 xenografts.Tumors treated with TRA RPT exhibited delayed growth and decreased proliferative activity, marked by Ki-67 immunohistochemistry. Aside from minor weight loss in select animals, no significant signs of radiotoxicity were observed in the kidneys or livers.Conclusions: We successfully demonstrated the clinical significance of TRA expression in human PCa, engineered and tested radiotheranostic agents to image and treat TRA + prostate CSCs.Ablation of TRA + CSCs blunted PCa growth.Future studies combining CSC ablation with standard treatment will be explored to achieve durable responses.
Bench-to-bedside development of multifunctional flexible embolic agents
Authors: Dawei Wang, Wei Rao
Journal: Theranostics (2023)

Transarterial chemoembolization (TACE) has been demonstrated to provide a survival benefit for patients with unresectable hepatocellular carcinoma (HCC).However, conventional TACE still faces limitations associated with complications, side effects, unsatisfactory tumor responses, repeated treatment, and narrow indications.For further improvement of TACE, additional beneficial functions such as degradability, drug-loading and releasing properties, detectability, targetability, and multiple therapeutic modalities were introduced.The purpose here is to provide a comprehensive overview of current and emerging particulate embolization technology with respect to materials.Therefore, this review systematically identified and described typical features, various functions, and practical applications of recently emerging micro/nano materials as particulate embolic agents for TACE.Besides, new insights into the liquid metals-based multifunctional and flexible embolic agents were highlighted.The current development routes and future outlooks of these micro/nano embolic materials were also presented to promote advancement in the field.